Exploiting aromatic interactions for β-peptide foldamer helix stabilization: a significant design element

Area of Science:

• Supramolecular Chemistry
• Organic Chemistry
• Biomolecular Engineering

Background:

• β-peptide oligomers are synthetic polymers with potential applications in biomaterials and drug delivery.
• Stabilizing secondary structures like helices in short oligomers is crucial for their function.
• Aromatic side-chains offer unique interaction possibilities for molecular design.

Purpose of the Study:

• To investigate the stabilization of tetrameric H10/12 helices in β-peptide oligomers using aromatic side-chains.
• To explore the self-assembly behavior of these stabilized helices in a polar medium.
• To assess the potential of these structures for bioactive foldamer construction.

Main Methods:

• Synthesis of β-peptide oligomers incorporating specific amino acid residues (ATENAC and ACHEC).
• Nuclear Magnetic Resonance (NMR) and Electronic Circular Dichroism (ECD) spectroscopy for structural analysis.
• Molecular modeling to understand intramolecular interactions.
• Transmission Electron Microscopy (TEM) to visualize self-assembly.

Main Results:

• Stable tetrameric H10/12 helix formation was achieved through intramolecular backbone-side chain CH-π interactions.
• Oligomers exhibited hydrophobically driven self-assembly into vesicle structures in polar media.
• The size of the self-assembled vesicles correlated with the number of aromatic side-chains.
• This represents the first observation of a stable H10/12 helix at tetrameric length.

Conclusions:

• Aromatic side-chains are effective for stabilizing H10/12 helical structures in β-peptides.
• The enhanced hydrophobic surface area promotes self-assembly into functional supramolecular structures.
• These findings provide a basis for designing novel H10/12 helices and bioactive foldamers with potential for receptor-ligand interactions.